Elsevier

The Lancet

Volume 371, Issue 9626, 24–30 May 2008, Pages 1800-1809
The Lancet

Review
Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies

https://doi.org/10.1016/S0140-6736(08)60768-0Get rights and content

Summary

Individuals with type 2 diabetes mellitus have increased cardiovascular disease risk compared with those without diabetes. Treatment of the residual risk, other than blood pressure and LDL-cholesterol control, remains important as the rate of diabetes increases worldwide. The accelerated atherosclerosis and cardiovascular disease in diabetes is likely to be multifactorial and therefore several therapeutic approaches can be considered. Results of mechanistic studies done in vitro and in vivo—animals and people—can provide important insights with the potential to improve clinical management decisions and outcomes. In this Review, we focus on three areas in which pathophysiological considerations could be particularly informative—ie, the roles of hyperglycaemia, diabetic dyslipidaemia (other than the control of LDL-cholesterol concentrations), and inflammation (including that in adipose tissue) in the acceleration of vascular injury.

Introduction

Several mechanisms are likely to contribute to the accelerated atherosclerosis and increased cardiovascular disease risk noted in patients with type 2 diabetes mellitus. We focus on areas in which basic mechanistic studies have high relevance to present clinical controversies to understand and address cardiovascular disease risk in people with diabetes. We assess pathophysiological information linking hyperglycaemia, diabetic dyslipidaemia (other than the control of LDL cholesterol concentrations), and inflammation to the accelerated vascular injury and cardiovascular disease risk in type 2 diabetes and discuss clinical considerations.

Section snippets

Hyperglycaemia and the vessel wall

Although a consistent association between glycaemic control and cardiovascular disease has been noted in epidemiological studies,1 the effect of tight glycaemic control did not seem to reduce the cardiovascular risk in clinical trials.2 Intensive glycaemic control in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study3 was stopped because of an increase in the number of cardiovascular deaths. A formal analysis of the results has not yet been reported. The ADVANCE (Action in

Diabetic dyslipidaemia and the vessel wall

Diabetic dyslipidaemia is strongly related to atherosclerosis. Even though patients with type 2 diabetes might not have substantially increased concentrations of LDL-cholesterol compared with matched individuals without diabetes, a cornerstone of the management of cardiovascular disease risk in diabetes is the use of LDL-cholesterol-lowering drugs—ie, statins. These drugs generally reduce cardiovascular disease events by 25–50%40, 41 but the excess residual cardiovascular disease risk remains

Glycaemia versus hyperlipidaemia in pathogenesis of atherosclerosis

The roles of hyperglycaemia and hyperlipidaemia in atherogenesis have been difficult to separate in animal models of diabetes. Hyperlipidaemia is usually exacerbated by the onset of hyperglycaemia—eg, in mouse models of LDL-receptor deficiency and apolipoprotein-E deficiency—thereby confounding the effect of hyperglycaemia. However, in two animal models, hyperglycaemia seems to have an independent role.90, 91 First, fat-fed diabetic pigs had more atherosclerosis than equally dyslipidaemic

Chronic subclinical inflammation and the vessel wall

Evidence ranging from pathological studies in people to in-vivo mouse models has established the role of inflammatory cells (such as macrophages and T lymphocytes) and inflammatory mechanisms (such as cytokine release) in the pathogenesis of atherosclerosis.92 Because type 2 diabetes and atherosclerosis are chronic conditions that take decades to arise, the cause and effect are difficult to discern (figure 3). Inflammation is implicated in the pathogenesis of type 2 diabetes and atherosclerosis.

Conclusions

Data from in-vitro and animal model studies support the argument that the absence of intensive glycaemic control in the ACCORD trial3 should not eliminate hyperglycaemia as an important therapeutic target for reduction of cardiovascular disease in diabetes; the absence of effect might relate to an unfavourable benefit to risk ratio of the presently available glucose-lowering treatments in the patients recruited for that trial. In the ACCORD trial,3 the elderly at risk patients might have had

Search strategy and selection criteria

We searched PubMed and Medline for all article types from January, 1957, to January, 2008. All languages were included. Search terms included “glucose”, “lipids”, “diabetes”, “vascular wall”, “atherosclerosis”, and “inflammation”. References were selected from journals on the basis of importance, novelty, and relevance. All article types were included. We gave priority to those that were published in the past 5 years in peer-reviewed journals.

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